Project Summary/Abstract Manganese (Mn) is a known neurotoxin that tens of thousands of workers are exposed to daily, but it is unknown if the current safety guidelines are appropriately strong or too weak to protect them. In an ideal world knowledge of the exposure history of an individual should allow to predict specific risks for health effects. To monitor the effect of Mn welding fumes on workers, the medical imaging techniques Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) are used to non-invasively image the structure, function, and neurochemistry in the human brain. However, currently studies are not making adequate strides in connecting Mn exposure to changes in MRI or MRS. Studies are only correlating Mn exposure to imaging parameters without taking into account the pharmacokinetic properties of the metal or the individual exposure history, thus lacking the ability to interpret individual data. The broad objective of this project is to fill this crucial gap by creating and validating mathematical models that take into account imaging data, pharmacokinetic properties of Mn and the individual exposure to Mn to predict individual effects of toxicity. Our group runs an ongoing, longitudinal neuroimaging study on local welders and matched controls. Thus we will have abundant and longitudinal data on brain MRI (e.g. T1 maps to assess the brain Mn burden), MRS data on several neurochemicals including GABA, data from personal air sampling and work history questionnaires, neurological and neuropsychological test results, and other biomarkers (toe nails, blood) at our disposal for modeling. The purpose of the current project is to assess and describe how knowledge on exposure and pharmacokinetic properties of Mn enables the interpretation of imaging data as quantitative brain Mn deposition, and how brain-region specific Mn deposition affects neurochemistry in other regions of the brain from where it is deposited. Aim 1 seeks to use MRI structural imaging and known pharmacokinetic properties of Mn to create a mathematical model that can determine the amount of Mn deposition in specific regions of the brain. Aim 2 investigates how the amount, the duration, and the location of Mn deposition in the brain affects neurochemistry. The results of this study will be a first step towards monitoring of individual risks from Mn toxicity by providing the necessary tools to translate exposure information to changes in the brain and consequent health symptoms. Importantly, a better interpretation of individual imaging data will also inform safety guidelines for the individual worker.